Open AccessDifferential regulation of IκB kinase α and β by two upstream kinases, NF-κB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1
Author(s) -
Hiroyasu Nakano,
Masahisa Shindo,
Sachiko Sakon,
Shigeyuki Nishinaka,
Motoyuki Mihara,
Hideo Yagita,
Ko Okumura
Publication year - 1998
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.95.7.3537
Subject(s) - map kinase kinase kinase , ask1 , mitogen activated protein kinase kinase , map2k7 , iκb kinase , kinase , cyclin dependent kinase 9 , cyclin dependent kinase 2 , c raf , cyclin dependent kinase 4 , microbiology and biotechnology , protein kinase a , biology , chemistry , signal transduction , nf κb
NF-κB is activated by various stimuli including inflammatory cytokines and stresses. A key step in the activation of NF-κB is the phosphorylation of its inhibitors, IκBs, by an IκB kinase (IKK) complex. Recently, two closely related kinases, designated IKKα and IKKβ, have been identified to be the components of the IKK complex that phosphorylate critical serine residues of IκBs for degradation. A previously identified NF-κB-inducing kinase (NIK), which mediates NF-κB activation by TNFα and IL-1, has been demonstrated to activate IKKα. Previous studies showed that mitogen-activated protein kinase/ERK kinase kinase-1 (MEKK1), which constitutes the c-Jun N-terminal kinase/stress-activated protein kinase pathway, also activates NF-κB by an undefined mechanism. Here, we show that overexpression of MEKK1 preferentially stimulates the kinase activity of IKKβ, which resulted in phosphorylation of IκBs. Moreover, a catalytically inactive mutant of IKKβ blocked the MEKK1-induced NF-κB activation. By contrast, overexpression of NIK stimulates kinase activities of both IKKα and IKKβ comparably, suggesting a qualitative difference between NIK- and MEKK1-mediated NF-κB activation pathways. Collectively, these results indicate that NIK and MEKK1 independently activate the IKK complex and that the kinase activities of IKKα and IKKβ are differentially regulated by two upstream kinases, NIK and MEKK1, which are responsive to distinct stimuli.